PROJECT SUMMARY The health burden of social disabilities and mood disorders including autism, depression, and anxiety is escalating rapidly, with an estimated cost of more than $500 billion per year. Despite the burden and the immense cost, the availability, efficacy, and tolerability of pharmacotherapies to treat these disorders are both limited and suboptimal. Neuropeptides are an important class of modulators for affective behaviors that have been widely implicated in mediating social behavior, stress, and anxiety. As a result, they have received considerable attention as possible therapeutics for social and mood disorders. The intranasal route is one of few potential routes for neuropeptide brain delivery. Several studies, however, have shown that the fraction of neuropeptide doses reaching the cerebral spinal fluid following intranasal neuropeptide administration is very low. This outcome could be attributed to the fact that neuropeptides have short half-lives and that only limited solution volumes can be administered intranasally. Thus, to date, testing of whether neuropeptides may be effective treatments for social and mood disorders has been limited by the difficulty of administering these molecules to the brain effectively. The objective of the proposed study is to establish a novel, RNA-based approach to efficiently deliver neuropeptides to the brain through intranasal administration. As a proof of concept, we will test the efficacy of our RNA-based intranasal approach to deliver the OXT peptide to the rat brain. We have recently validated a first rat model for autism, the Shank3-deficient rat, and demonstrated that OXT improves social and attentional deficits in this rat. To test the functionality of the delivered OXT, we will leverage the Shank3-deficient rat model and assess the ability of the OXT, delivered intranasally using our RNA-based approach, to reverse the social behavior deficits in this model. The proposed study will be the first ever to test the efficacy of an RNA-based approach to delivering a functional neuropeptide to the brain. It will lay the foundation for future studies that will test the efficacy of our novel platform to deliver several other neuropeptides, alone or together, that are of potential therapeutic value for brain-based disorders. Importantly, findings from this study will set the ground for the development of a novel and innovative clinically-relevant therapeutic approach that is urgently needed to overcome the limitations of neuropeptide delivery to the human brain.